Ann Nucl Med (2008) 22:557–564
DOI 10.1007/s12149-008-0156-x

ORIGINAL ARTICLE

Usefulness of rCBF analysis in diagnosing Parkinson’s disease:
supplemental role with MIBG myocardial scintigraphy
Shigeki Nagamachi · Hideyuki Wakamatsu
Shogo Kiyohara · Seigo Fujita · Shigemi Futami
Shozo Tamura · Masamitsu Nakazato
Syuichi Yamashita · Hideo Arita · Ryuichi Nishii
Keiichi Kawai

Received: 8 May 2007 / Accepted: 4 February 2008
© The Japanese Society of Nuclear Medicine 2008

Abstract
123
I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for differentiating idiopathic
Parkinson’s disease (PD) from parkinsonism (PS) causedby other disorders. However, cardiac MIBG uptake isaffected by various causes. Alternatively, hypoperfusionin the occipital lobe of PD is reported recently.
Objective The objective is to clarify the correlation
between regional cerebral blood flow (rCBF) alterationand cardiac MIBG uptake in PD. In addition, we
examined whether additional brain perfusion analysis
improved the differential diagnostic ability for PD fromPS when compared with MIBG scintigraphy alone.
Methods Forty-nine patients with PD (27 mild groups:
Hoehn and Yahr stages I, II; 22 severe groups: Hoehn
and Yahr stages III, IV) and 28 patients with PS participated. We compared absolute rCBF values between PD
and PS. In addition, we determined correlation between
MIBG parameters and each rCBF value. Finally, we
compared the diagnostic ability for the differentiation of

PD from PS between two diagnostic criteria, each MIBG
index abnormality alone [heart-to-mediastinum ratio,
H/M (E) < 1.9, H/E (D) < 1.7, washout rate > 40%] andeach MIBG index abnormality or occipital lobe hypoperfusion (<36 ml/100 g per min).
Results Absolute rCBF value of occipital lobe was significantly lower in severe PD as compared with PS or
mild PD. In the correlation analysis, rCBF of occipital
lobe correlated positively with MIBG parameters (H/M).
Regarding the diagnostic ability, sensitivity improved byaccounting for occipital hypoperfusion as compared withMIBG indices alone. In contrast, neither specificity nor
accuracy improved by adding occipital lobe analysis.
Conclusions MIBG parameters (H/M) correlated positively with occipital hypoperfusion in PD. In the differential diagnosis between PD and PS, although its
usefulness might be limited, analysis of rCBF in theoccipital lobe added to 123I-MIBG myocardial imaging
can be recommended.
Keywords 123I-MIBG · 99mTc-HMPAO · 3D-SSP · 3DSRT · Parkinson’s disease

S. Nagamachi (*) · H. Wakamatsu · S. Kiyohara · S. Fujita ·S. Futami · S. Tamura · H. Arita
Department of Radiology, Miyazaki Medical College, 5200
Kihara, Kiyotake, Miyazaki-gun, Miyazaki 889-1692, Japane-mail: snagama@med.miyazaki-u.ac.jp
M. Nakazato · S. Yamashita
Department of 3rd Internal Medicine, Miyazaki Medical
College, Miyazaki, Japan
R. Nishii
Shiga Medical Center for Adults, Shiga, JapanK. Kawai
Faculty of Health Science, School of Medicine, Kanazawa
University, Ishikawa, Japan

Introduction
Idiopathic Parkinson’s disease (PD) is characterized byseveral cardinal symptoms, including resting tremor,
rigidity, bradykinesia, and postural instability. However,there are no absolute indicators for diagnosing PD
because the initial symptoms of PD may change withthe onset, and the clinical diagnosis is sometimes difficult[1, 2].
In addition to the aforementioned characteristic
symptoms, autonomic abnormalities have frequently

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been noted in PD [3]. Earlier, [123I] metaiodobenzylguanidine (MIBG) myocardial scintigraphy was used as an
imaging method to evaluate sympathetic nerve terminals[4]. Recently, MIBG myocardial uptake is reported to
be decreased in patients with PD regardless of the presence of orthostatic hypotension [5–8]. Clinically, MIBG
myocardial scintigraphy is a useful tool for differentiating PD from parkinsonism (PS) caused by other disorders [5, 9]. However, cardiac MIBG uptake is known to
be decreased in various diseases other than PD [10–13].
Other effective imaging methods, therefore, are necessary to overcome such drawbacks. One of the alternative
imaging methods is measuring the concentration of
striatal dopamine reuptake transporters such as 123I-βCIT single-photon emission computed tomography(SPECT) [14, 15]. However, such pharmaceuticals arecommercially available in only a few countries, and are
not commonly available in Japan.
Recently, regional cerebral blood flow (rCBF) alteration of PD using brain perfusion SPECT has beenreported [16–21]. PD with autonomic nerve impairment
showed hypometabolism in the parieto-occiptal lobe
[22–24]. Bohnen et al. [20] reported a correlation between
glucose metabolism and the severity of motor impairment. Notably, Abe et al. [25] reported occipital andposterior parietal hypoperfusion in PD patients without
dementia using N-isopropyl-p-[(123) I] iodoamphetaminerCBF SPECT.
Here, we investigated the correlation between rCBF
distribution and MIBG indices in PD. In addition, we
examined whether additional brain perfusion SPECT
analysis could improve the ability to differentiate PD
from PS as compared with 123I-MIBG myocardial scintigraphy alone.

Materials and methods
Patients
Fifty patients with PS were recruited for the present
study. Finally, we studied 49 idiopathic PD patients and28 patients with PS owing to other diseases. The final
diagnosis of those with PS was 14 multiple system
atrophy (MSA-P), 5 progressive supranuclear palsy,
4 corticobasal degeneration, 3 drug-induced PS, and2 essential tremor. PS with cerebrovascular disease was
excluded.
Parkinson’s disease was diagnosed if a patient had
resting tremor, cogwheel rigidity, and bradykinesia. The
PD patients did not have a supranuclear gaze abnormality, myoclonus, automatic dysfunction, apraxia, ordementia. No patients showed pseudopsia clinically. The

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Ann Nucl Med (2008) 22:557–564

severity of patients’ motor impairment was gradedaccording to the Hoehn and Yahr (H&Y) staging system[26]. All PD patients were categorized into two groups,
severe stage (H&Y III, IV) and mild stage (H&Y I, II).
Patients’ cognitive functions were evaluated by MiniMental State Examination to exclude Parkinson’s disease
with dementia (PDD) or diffuse Levy body disease(DLB) [27–29].
None of the participants had any cardiac symptoms
including bradycardia, tachycardia, chest oppression
and pain, or significant arrhythmia. Electrocardiography, chest roentgenography, ultrasonic cardiography,
and blood examinations including thyroid function
were also performed and none of the patients showed
any abnormality including diabetes mellitus on these
examinations.
123

I-MIBG myocardial imaging

Following a 20-min resting period, patients received an
intravenous injection of 111 MBq of 123I-MIBG (FUJIFILM RI Pharma, Tokyo, Japan). A planar image ofthe chest view was obtained in an anterior view for 5 minwith a dual-head eCAM r-camera (Siemens, New York,NY, USA) after 15 min for the early image and after 4 h
for the delayed examination. The photopeak energy wascentered at 159 keV with a 20% window. Relative 123IMIBG organ uptake was determined by setting theregion of interest on the anterior view. Average counts
per pixel in the heart and mediastinum were used to
calculate the heart-to-mediastinum (H/M) ratio. Cardiac
MIBG washout rate (WR) was defined as the percent
change in activity from the early image to the delayed
image within the left ventricle.
We previously performed cardiac MIBG imaging innormal subjects (n = 20, mean age 58.8 ± 5.2, range 43–66). In these patients, the mean early H/M was 2.3 ± 0.3,
the mean delayed H/M was 2.1 ± 0.2, and the mean WR
was 25 ± 5.3%.
99m

Tc-HMPAO-SPECT

Prior to undergoing SPECT, all subjects received an
intravenous line while lying down with their eyes closed.
Each subject received a 600-MBq intravenous injectionof 99mTc-HMPAO (PAO). A dynamic study was done forcalculating the absolute rCBF value using graphic analysis; 10 min following this injection, a brain SPECT was
performed using a triple-head gamma camera (Prism
3000: Marconi) equipped with a high-resolution fanbeam collimator. For each camera, projection data wereobtained in a 128 × 128 format for 24 angles of 120° at
50 s per angle. A Shepp and Logan Hanning filter was

Ann Nucl Med (2008) 22:557–564

559

used for SPECT image reconstruction at 0.7 cycles per
centimeter. Attenuation correction was performed using
Chang’s method.
The global CBF was non-invasively measured usinggraphic analysis as described earlier without blood
sampling [30]. The SPECT data were transferred to apersonal computer with the interface software via the
network for both 3D-SSP and 3D-SRT analyses. In 3DSSP analysis, we used adjusted rCBF images (normalization of global CBF for each subject to 50 ml/100 g per
minute with proportional scaling) to compare the relative rCBF in each group. Each of three groups was compared using unpaired t test. The areas whose Z scoreexceed 4.53 were defined as areas showing abnormalrCBF distribution. We also demonstrated decreasedrCBF distribution with Z score over 2. In addition, absolute rCBF values of each cerebral cortex and basal
ganglia were calculated using 3D-SRT [31]. We compared those absolute rCBF values respectively between
three groups. And we examined which regions’ rCBF
abnormality was specific for PD.
To clarify the association between cardiac sympathetic nerve involvement and rCBF alteration, we analyzed the correlation between MIBG parameters andeach cortical rCBF value.
Finally, we compared the diagnostic ability to differentiate PD from PS between two diagnostic criteria,
patient is PD when each MIBG index is abnormal [H/M
(E) <1.9, H/M (D) <1.7, WR > 40%] and that patient is
PD when each MIBG index is abnormal or rCBF alteration (<36.0 ml/100 g per minute) existed. We determinedthe cut-off values of MIBG parameters and rCBF whenaccurate in differentiating PD from PS.
Statistical analysis
Correlations were analyzed using Spearman’s andPearson’s correlation coefficients and expressed using

linear regression curves. The Bonferroni–Dunn test wasused for intergroup differences of rCBF or MIBG
parameters among PD subgroup and PS.

Results
Patients’ characteristics are listed in Table 1. Neither age
nor sex was statistically significantly different among thethree groups. In PD, both H/M (E) and H/M (D) weresignificantly lower than those of PS. WR of PD withsevere stage was significantly higher than that of PS.
Within the PD group, both H/M (E) and H/M (D) in thesevere stage group were significantly lower than thoseof the mild stage group. Although the value of WR inthe severe stage group was markedly increased in thesevere stage group as compared with the mild stage
group, the difference was not statistically significant(Table 1, Fig. 1).
The 3D-SSP analyses demonstrated that the severe
PD group showed prominently decreased rCBF in theoccipital lobe when compared with the PS group. A
decrease in rCBF was also noted in the occipital lobe andin a part of the parietal lobe in severe PD as comparedwith the mild stage group (Figs. 2, 3).
According to the results of 3D-SRT analysis, theabsolute rCBF value of the bilateral occipital lobes was
significantly lower in the severe stage PD group as compared with PS or mild stage PD. Absolute values ofrCBF in the other regions did not differ significantly. In
contrast, rCBF of mild stage PD was almost equal tothat of PS (Table 2).
In the correlation analysis, rCBF of both occipital
lobes significantly correlated positively with H/M parameters in PD. However, there was no significant correlation between WR and rCBF of the bilateral occipital
lobes. Although rCBF of other regions also correlated
positively with H/M, their correlation coefficients wereTable 1 Comparison of clinical characteristics and 123I-metaiodobenzylguanidine (MIBG) indexes
PD (n = 49)

AgeSex (M : F)
Duration (y) (MIBG indices)
H/M (E)
H/M (D)
WR (%)HY I or II (n = 27)

HY III or IV (n = 22)

66.0 ± 9.3
12 : 156.1 ± 5.2
1.81 ± 0.43*,**
1.61 ± 0.56*,**40.7 ± 12.7***

71.6 ± 7.7
11 : 119.6 ± 5.3
1.36 ± 0.49*
1.13 ± 0.51*
47.5 ± 17.3***

PS (n = 28)

P64.5 ± 7.2
12 : 167.4 ± 2.1
2.36 ± 0.52
2.42 ± 0.85
26.3 ± 12.2

NS
NS
NS
<0.01
<0.01
<0.01

PD Parkinson’s disease, PS parkinsonism, H/M heart-to-mediastinum ratio, WR washout rate
* Statistically significantly lower than PS** Statistically significantly higher than HY III or IV*** Statistically significantly higher than PS

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Ann Nucl Med (2008) 22:557–564

H/M(E)

H/M(D)

3.5

4

3

3.5

WR(%)

3

2.5

2.5

2

2
1.5
1.5
1

1

.5

.5

0

0

PD(I,II) PD(III,IV) PS:P<0.05,

PD(I,II) PD(III,IV)PS:P<0.01

Fig. 1 Comparison of 123I-metaiodobenzylguanidine (MIBG)
indices among parkinsonism (PS) and Parkinson disease (PD)subgroups were demonstrated. Both PD subgroups showed

Table 2 Comparison ofregional cerebral blood flow(rCBF; absolute value,
ml/100 g per minute)* Statistically significantly
lower than PS or PD HY(I, II)

Occipital (R)Occipital (L)Frontal (R)Frontal (L)Temporal (R)Temporal (L)Parietal (R)Parietal (L)Basal ganglia (R)Basal ganglia (L)significantly low heart-to-mediastinum ratio (H/M) and highwashout rate as compared with those of the PS group

PD HY (I, II) (n = 27)

PD HY (III, IV) (n = 22)

PS (n = 28)

39.9 ± 8.2
39.7 ± 8.5
42.8 ± 8.6
41.8 ± 11.0
40.1 ± 12.3
40.7 ± 11.7
41.6 ± 10.2
41.6 ± 11.8
40.6 ± 10.7
40.4 ± 11.0

34.4 ± 6.8*
34.5 ± 7.2*
39.9 ± 8.8
38.9 ± 9.3
38.5 ± 9.2
38.7 ± 9.3
38.6 ± 10.2
39.2 ± 9.8
39.2 ± 6.8
39.3 ± 6.6

41.1 ± 11.2
41.2 ± 12.8
42.5 ± 8.2
42.7 ± 9.0
40.9 ± 11.2
40.5 ± 9.4
41.7 ± 7.6
42.8 ± 8.0
39.8 ± 7.2
40.2 ± 8.7

relative weak when compared with those of rCBF in theoccipital lobe (Table 3).
Regarding the ability to differentiate PD from PS,
sensitivity improved by accounting for occipital lobe
hypoperfusion in comparison with MIBG parameters
analysis alone (81.6% vs. 75.5%, 81.6% vs.77.6%, and87.8% vs. 71.6%). However, neither specificity nor accuracy improved (Table 4). When comparing severe PD
with PS, the values of each diagnostic parameter
improved. They also showed some improvement in thesensitivity (95.5% vs. 90.1%, 100% vs. 95.5%, and 95.5%
vs. 86.3%) by combining MIBG and rCBF analysis,
respectively. Neither specificity nor accuracy improved(Table 5).

13

PD(I,II) PD(III,IV)PS

Table 3 Correlation coefficient between absolute rCBF and MIBG
indexes in PD
RegionH/M (E)

H/M (D)WR

Rt occipital
Lt occipital
Rt frontal
Lt frontal
Rt temporal
Lt temporalRt parietal
Lt parietal
Rt basal ganglia
Lt basal ganglia

0.61
0.62
0.51
0.52
0.36
0.37
0.49
0.49
0.51
0.53

0.64
0.61
0.53
0.56
0.45
0.45
0.52
0.52
0.54
0.57

0.35
0.32
0.20
0.22
0.12
0.13
0.15
0.16
0.24
0.29

WR washout rate

Ann Nucl Med (2008) 22:557–564
Fig. 2 Results of two-groupcomparison between PS and
PD subgroups by 3D-SSP
analysis. The regions with Z
score over 4.53. Upper row
The results of two-groupcomparison between severe
PD and PS. Severe PD
demonstrated significant
decreased occipital perfusion.
Middle row The results of
two-group comparison
between mild PD and PS. No
significant rCBF difference isnoted. Lower row The resultsof two-group comparison
between severe PD and mild
PD. Significant regional
cerebral blood flow (rCBF)
decrease of occipital lobe isnoted in severe PD

Fig. 3 Results of two-groupcomparison between PS and
PD subgroups using 3D-SSP
analysis. Abnormal rCBF
areas with Z score over 2.0.
Upper row The results of twogroup comparison between
severe PD and PS. Severe PD
demonstrated prominent
occipital hypoperfusion.
Middle row The results of
two-group comparison
between mild PD and PS.
Localized hypoperfusion of
occipital lobe is noted. Lower
row The results of two-groupcomparison between severe
PD and mild PD. ProminentrCBF decrease in occipital
lobe is noted in severe PD
Table 4 Comparison ofdifferential diagnostic ability
for PD (whole patients)from PS

Low occipital rCBF:<36 ml/100 g per minute
Table 5 Comparison ofdifferential diagnostic ability
for PD (HY III, IV) from PS

Low occipital rCBF:<36.0 ml/100 g per minute561

PD (HYIII,IV) < PS

PD (HYI,II) < PS

PD (HYIII,IV) < PD (HYI,II)PD (HYIII,IV) < PS

PD (HYI,II) < PS

PD (HYIII,IV) < PD (HYI,II)Low H/M (E) (<1.9)
Low H/M (E) or low-occi rCBF
Low H/M (D) (<1.7)
Low H/M (D) or low-occi rCBFHigh WR (>40%)
High WR or low-occi rCBF
Low-occi rCBF

Low H/M (E) (<1.9)
Low H/M (E) or low-occi rCBF
Low H/M (D) (<1.7)
Low H/M (D) or low-occi rCBFHigh WR (>40%)
High WR or low-occi rCBF
Low occipital rCBF

Sensitivity

Specificity

Accuracy

75.5
81.6
77.6
81.6
81.6
87.8
55.2

89.3
82.1
85.7
75.0
89.3
75.0
85.7

80.5
80.5
80.5
79.1
84.4
83.1
67.5

Sensitivity

Specificity

Accuracy

90.1
95.5
95.5
100.0
86.3
95.5
77.3

89.3
78.5
85.7
71.4
89.3
75.0
85.7

90.0
86.0
90.0
84.0
88.0
84.0
82.0

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Discussion
In PD, the entire autonomic nervous system is affected,
including the hypothalamus, parasympathetic system,and sympathetic system [32]. Evidence indicates thatcardiac uptake of MIBG is reduced in PD, even early inthe clinical course [33, 34]. Early uptake of myocardial
MIBG likely reflects presynaptic sympathetic system
integrity and distribution, whereas delayed uptake inaddition may reflect the functional status or washout of
norepinephrine from sympathetic nerve terminals given
the presence of pathological changes [9]. MIBG myocardial scintigraphy, therefore, has been found to contribute to the differential diagnosis between PD and otherforms of PS [9, 32]. Our results supported these earlier
reports, and the phenomenon was observed in the severe
PD group in particular. However, one limitation is that
we cannot use the examination in the presence of abnormal cardiac function, such as in patients with heart
failure or diabetes mellitus.
Alternatively, although not specific, rCBF analysis is
known to be helpful in characterizing PD [16, 35]. An
earlier study reported that global CBF in PD was uniformly lower than that in healthy volunteers [35]. Regarding the connection with H&Y staging, rCBF in the severe
stage (H&Y III, IV) is lower than in the mild stage (H&Y
I, II) [35]. The results of the present study using 3D-SRT
analysis agreed with the earlier report. In addition,
recent studies showed that both hypometabolism andhypoperfusion of the occipital lobe are the characteristics of PD [22–24]. Arahata et al. [22, 36] reported that
PD with autonomic nerve disturbance represents occipital lobe hypoperfusion. This study also agreed well withthe results of a report on the use of statistical parametric
imaging method (3D-SSP). Moreover, absolute occipitalrCBF correlated positively with H/M. On the basis ofthese results, occipital lobe low perfusion is likely toreflect the seriousness of the pathological condition of
PD. The reason for the modest correlation coefficient
may be that occipital lobe disability does not always coexist with cardiac sympathetic nerve disorder. Aggravation of the severity of the two conditions seems not toaccord in the early stages of PD.
Thus, occipital rCBF analysis seemed to have a meaningful role in diagnosing PD, whereas there were no significant differences in rCBF in the frontal lobe, basal
ganglia parietal lobe, or temporal lobe between PD and
PS. 18F-DOPA-PET studies have described decreased
uptake in the caudate nucleus or frontal cortex in PD[37, 38]. Dysfunction of the dopamine nervous system
including striatal region is well known. However, in thepresent study by 3D-SRT analyses, selective rCBF
decrease in these areas was not observed. This discor-

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Ann Nucl Med (2008) 22:557–564

dance between rCBF and dysfunction of caudate nucleus
has also been reported [36].
As described earlier [9], when using MIBG scintigraphy analysis alone, the differential diagnostic ability isquite good, with the diagnostic ability of every index
being around 80–90% in severe PD. When we use combined diagnosing criteria, abnormal MIBG indices or
occipital lobe hypoperfusion, only sensitivity improved.
However, both specificity and accuracy deteriorated orremained unchanged. One of the possible reasons is thedisease severity of PD. As rCBF in the occipital cortex
is usually higher physiologically than that in othercortices [39, 40], it is difficult to identify occipital lobe
hypoperfusion in mild cases [41, 42]. Hence, the selective
hypoperfusion of the occipital lobe when compared with
PS was noted mainly in severe stage PD. This phenomenon seemed to be observed dependent on the stage ofthe disease. Another influential factor is disorders
included in the PS group. In this study, all false-positive
cases with low occipital rCBF were composed of MSAP. Differential diagnosis between MSA-P and IPD is
known to be very difficult and the final diagnosis in somecases is made only at autopsy [43]. Although Matsui
et al. [23] reported a similar result by 3D-SSP with small
patient numbers; the diagnostic capability was notaddressed [23]. We should take into account that there
is a significant overlap of cerebral blood flow values
between the two groups.
Thus, additional occipital lobe rCBF analysis did notalways improve diagnostic capability in comparison
with that by MIBG alone after all. Therefore, the clinicalimplication of additional occipital lobe rCBF analysis isconsidered as follows, it would be effective, having recognized that possible MSA-P cannot be always excluded
from the differential diagnosis. In addition, in cases withcomplicating cardiac disease such as heart failure or
diabetic autonomic neuropathy which disturbs MIBG
interpretation, rCBF analysis might be helpful for either
screening or ruling out a diagnosis. Thus, additionalrCBF analysis might be restrictive and should be chosen
dependent on limited conditions. However, as the occipital lobe rCBF is associated with the severity of PD, it
might be useful for monitoring disease progression.
The precise mechanism of the hypoperfusion in occipital lobe had not been clarified yet. One explanation isthat visual cognitive function is disturbed earlier thanother cognitive functions in PD [40]. Retinal dopamine
nerve deletion is also present [34]. Hypoperfusion of theoccipital lobe is likely to be related to these clinical background factors. In PDD, hypoperfusion or hypometabolism of the occipital lobe, parietal lobe and cingulate
gyrus are known [34]. Because all our subjects insevere stage PD were free from dementia, occipital hypo-Ann Nucl Med (2008) 22:557–564

perfusion was not considered to be associated withdementia. Pathologically, DLB, PDD, and PD constitute a part of a pathological continuum [43]. Glucose
metabolism in DLB is similar to that in PDD [44]. Therefore, the differential diagnosis of these Lewy body diseases is difficult and also is the most important problem.
There is still a possibility that we might detect a case of
PD progressing to PDD in the near future. Serial followup studies should preferably be done by these two
methods to resolve these issues in future.

Conclusions
The MIBG parameters, both H/M (E) and H/M (D),were positively correlated with occipital lobe hypoperfusion in PD. In the differential diagnosis between PD and
PS, although the utility might be limited, the analysis ofrCBF in the occipital lobe in addition to 123I-MIBG myocardial imaging would be helpful.

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